Excitatory amino acids such as L-glutamate (Glu) and L-aspartate (Asp), are major neurotransmitters in the mammalian central nervous system. Multiple acidic amino acid receptor subtypes exist for these acid amino acid neurotransmitters. For example, these include ion channel-linked receptors mediating neuronal depolarization, named after the protypical agonists N-methyl-D-aspartate (NMDA), alpha-amino-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and a putative presynaptic stimulator, L-2-amino-4-phosphonobutyrate (L-AP4). A fifth excitatory amino acid receptor is the metabotropic receptor, linked to phosphoinositide metabolism (Farooqui and Horrocks, Brain Res. Rev. 16, 171, 1991).
NMDA receptors play a specialized role due to the unique properties of their linked ion channels and participate in various plastic neuronal events including initiation of long-term potentiation, which is a proposed substrate of learning and memory and the establishing of synaptic contacts during neuronal development. NMDA receptors are also involved in other processes such as the transmission of sensory information (MacDermott and Dale, Trends Neurosci. 10, 280, 1987).
Apart from their important physiological roles, excitatory acidic amino acids such as NMDA are also involved in pathophysiological events in the central nervous system.
Abnormally low levels of glutamic acid (Glu) can compromise normal levels of excitation and cause, for example, learning and memory deficits. Excessive levels of Glu can produce toxic effects. The term "excitotoxicity" was coined by Olney (in Hyhan W. L. [ed]: "Heritage Disorders of Amino Acids Metabolism" New York: Macmillan pp. 501-512, 1989) to describe the process by which excitatory amino acids can cause neuronal cell death.
Evidence indicates that NMDA receptors exist in the peripheral tissues and that activation of these receptors may be involved in a mechanism of lung and other organ injury (Said, S. I. et al., Letters to Neuroscience, 65, 943-946, 1995). This cytotoxic process is mainly mediated by an over-stimulation of NMDA receptors and may occur in cases of cerebral stroke, cerebral ischaemia, epilepsy, Alzheimer's disease, AIDS-related dementias, traumatic brain injury and other neurodegenerative disorders (Olney, Ann. Rev. Pharmacol. Toxicol. 30: 47-71, 1990; Foster et al, in "Current and future Trends in Anticonvulsant, Anxiety and Stroke Therapy" Wiley-Liss, Inc. pp. 301-329, 1990; Rogawski and Porter, Pharmacol. Rev., 42: 223-286, 1990).
The NMDA receptor comprises several binding domains that interact with each other for proper functioning and modulation of nerve cell activity. It is theorized that the NMDA receptor forms a complex acting as a receptor-linked ion channel. Essentially, the function of the receptor is to bind NMDA or the natural amino acids, Glu or Asp, and open an associated ion channel that allows the entry of sodium (Na.sup.+) and calcium (Ca.sup.2+) into the stimulated neuron as well as the exit of potassium (K.sup.+).
Whereas the ion channels of other excitatory amino acid receptors (AMPA, kainate and L-AP4) are only permeable to Na.sup.+ and K.sup.+, the NMDA receptor channel is also permeable to Ca.sup.2+. This feature may be of importance for the proposed role of this receptor in both short and long-term plasticity such as learning, memory and neuropathology.
Intracellular Ca.sup.2+ is responsible for the regulation of a large variety of cellular activities (Farooqui and Horrocks, Brain Res. Rev. 16, 171; 1991). An overstimulation of brain NMDA receptors, observed in cases of anoxia, ischaemia and hypoglycemia, results in a build-up of the concentration of Ca++ in stimulated neurons and a cascade of intracellular events (activation of phospholipases [PLA.sub.2, PLC], lipases, proteases and endonucleases) that lead to neuronal cell death (Farooqui and Horrocks, Brain Res. Rev. 16, 171; 1991).
There is therefore a need for compounds which can bind or antagonize the NMDA receptor complex or otherwise protect neurons against excitatory amino acid receptor-induced degeneration.